Many ways of preparing and formulating drugs have been developed in order to facilitate gradual release of a drug over time. Conventional "timed release" formulations have typically involved coated tablets which after dissolution of the coating release the entire drug contents of the tablet. Thus, drug concentrations in the blood rapidly reach a peak and then decrease at a rate determined by the metabolic half-life in the body. The need to reshape this profile by eliminating the initial peak, and thus any resulting toxic or other undesirable side effects, has led to the developement of more sophisticated controlled release formulations. In many cases, the desired release pattern is "zero order", i.e., the release rate is approximately constant for most of the drug delivery period.
It has been demonstrated that controlled drug release can be achieved by using a polymer matrix as a drug "reservoir". In general, the drug release rate Q.sub.t (release amount/time) in such devices is proportional to S.multidot..DELTA.C/1, where S is the active surface area; i.e., the area through which drug actually passes (and can be considered as either the area of interface between undepleted and partially depleted regions for solute in the device or the area of membrane that controls overall diffusion rate), .DELTA.C is the concentration gradient, and 1 is the diffusion length of solute through device. Some drug reservoir devices that have been developed maintain approximately zero order drug release due to constant S, .DELTA.C, and 1.
Geometry considerations can also be introduced in order to control the concentraion profile. For example, as discussed by Lee in Proc. Int. Sym. Contr. Rel. Bioact. Mater. 10:136 (1983), drug release can be maintained at an approximately constant rate if .DELTA.C/1 increases as S decreases in drug-loaded polymeric beads.
In addition, zero order release has been obtained using "Case II Diffusion Systems" i.e., where drug diffusion is much faster than polymer relaxation, or swelling (M.sub.t /M.sub..infin. =kt.sup.n, where n=1, M.sub.t is the total released amount of drug at the time t, and M.sub..infin. is the total released amount of drug at time infinity). Such systems are described, for example, by Lee, supra, and by Korsmeiyer, Proc. Int. Sym. Contr. Rel. Bioact. Mater. 10:141 (1983).
Barriers, or release rate controlling membranes, have also been introduced as a way of effecting zero order release. The barrier concept was introduced by Cowsar et al., ACS Symposium Series 31:180 (1976), who coated the surface of a hydrogel containing sodium fluoride with a hydrogel having a lower water content. Kim et al., J. Mem. Sci. 7:293 (1980), disclosed monolithic devices for the controlled release of progesterone, the devices comprising copolymers of poly(2-hydroxyethylmethacrylate) (pHEMA), poly(methoxyethoxyethyl methacrylate) and/or poly(methoxyethyl methacrylate). The devices were soaked in an ethanol solution of ethylene glycol dimethacrylate (EGDMA), followed by exposure to ultraviolet light to create a crosslinked zone at the outer surface. Devices with such surface barriers can approximate zero order release, where the release rate is controlled by the thickness of the barrier layer and its water content.
The inventors herein now propose the use of an interpenetrating polymer network for use in achieving pseudo-zero order drug release, i.e., a near-constant release rate for a significant portion of the release phase. Other types of drug release profiles, should they be desired, may also be provided using the IPNs disclosed herein. Interpentrating polymer networks have been described in the literature, e.g., by K. F. Mueller and S. J. Heiber, J. Appl. Polymer Sci. 27:4043-4064 (1982), S. C. Kim et al., J. Appl. Polymer Sci. 5:1289 (1977), and L. H. Sperling and D. W. Friedman, J. Polymer Sci. A-2(7): 425 (1969). As described in the Mueller et al. article, in an IPN, one preformed crosslinked polymer matrix actually contains a second polymer which penetrates the matrix throughout but is not covalently bound to it. IPNs may be prepared by either simultaneous or sequential synthesis. In sequential synthesis, a selected monomer is diffused throughout a preformed crosslinked matrix and then polymerized within it. In simultaneous synthesis, the mixture of monomers, prepolymers, linear polymers, crosslinkers, initiators, and the like, for both component networks, form a homogenous fluid. Both components are then simultaneously polymerized and/or crosslinked by independent, noninterfering reactions.
Potential uses of IPNs in drug formulations and in drug delivery in general remain to a large extent undeveloped. The inventors hering now propose the use of heterogeneous IPNs (HTIPNs), i.e., an IPN which contains both hydrophilic and hydrophobic domains, to provide a controlled release drug device such that the degree of drug loading as well as the overall drug release profile can be carefully controlled.